Carbomer-based adjuvant elicits CD8 T-cell immunity by inducing a distinct metabolic state in cross-presenting dendritic cells.
ATP Binding Cassette Transporter, Subfamily B, Member 2
/ physiology
Acrylic Resins
/ chemistry
Adjuvants, Immunologic
/ pharmacology
Animals
Antigen Presentation
/ drug effects
CD8-Positive T-Lymphocytes
/ drug effects
Dendritic Cells
/ drug effects
Kruppel-Like Transcription Factors
/ genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidase 2
/ physiology
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
05
06
2020
accepted:
16
11
2020
revised:
27
01
2021
pubmed:
15
1
2021
medline:
27
4
2021
entrez:
14
1
2021
Statut:
epublish
Résumé
There is a critical need for adjuvants that can safely elicit potent and durable T cell-based immunity to intracellular pathogens. Here, we report that parenteral vaccination with a carbomer-based adjuvant, Adjuplex (ADJ), stimulated robust CD8 T-cell responses to subunit antigens and afforded effective immunity against respiratory challenge with a virus and a systemic intracellular bacterial infection. Studies to understand the metabolic and molecular basis for ADJ's effect on antigen cross-presentation by dendritic cells (DCs) revealed several unique and distinctive mechanisms. ADJ-stimulated DCs produced IL-1β and IL-18, suggestive of inflammasome activation, but in vivo activation of CD8 T cells was unaffected in caspase 1-deficient mice. Cross-presentation induced by TLR agonists requires a critical switch to anabolic metabolism, but ADJ enhanced cross presentation without this metabolic switch in DCs. Instead, ADJ induced in DCs, an unique metabolic state, typified by dampened oxidative phosphorylation and basal levels of glycolysis. In the absence of increased glycolytic flux, ADJ modulated multiple steps in the cytosolic pathway of cross-presentation by enabling accumulation of degraded antigen, reducing endosomal acidity and promoting antigen localization to early endosomes. Further, by increasing ROS production and lipid peroxidation, ADJ promoted antigen escape from endosomes to the cytosol for degradation by proteasomes into peptides for MHC I loading by TAP-dependent pathways. Furthermore, we found that induction of lipid bodies (LBs) and alterations in LB composition mediated by ADJ were also critical for DC cross-presentation. Collectively, our model challenges the prevailing metabolic paradigm by suggesting that DCs can perform effective DC cross-presentation, independent of glycolysis to induce robust T cell-dependent protective immunity to intracellular pathogens. These findings have strong implications in the rational development of safe and effective immune adjuvants to potentiate robust T-cell based immunity.
Identifiants
pubmed: 33444400
doi: 10.1371/journal.ppat.1009168
pii: PPATHOGENS-D-20-01207
pmc: PMC7840022
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B, Member 2
0
Acrylic Resins
0
Adjuvants, Immunologic
0
Klf2 protein, mouse
0
Kruppel-Like Transcription Factors
0
Tap1 protein, mouse
0
carbomer
0
Cybb protein, mouse
EC 1.6.3.-
NADPH Oxidase 2
EC 1.6.3.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009168Subventions
Organisme : NIAID NIH HHS
ID : U01 AI124299
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014520
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM135066
Pays : United States
Organisme : NIH HHS
ID : S10 OD018039
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM108538
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA188034
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205101
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI149793
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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